Sulfated 11beta-methyl estrogens

ABSTRACT

THE ABOVE-CAPTIONED COMPOUNDS ARE PRODUCED FROM 3HYDROXY-11B-METHYLESTRA-1,3,5(10)-TRIEN-17-ONE BY SUCCESSIVE REACTIONS WITH SULFAMIC ACID IN PYRIDINE AND AN ALKALI METAL HYDROXIDE AND ARE USEFUL PHARMOCOLOGICAL AGENTS, E.G. ESTROGENS.

United States Patent 01 hoe 3,657,290 Patented Apr. 18, 1972 3,657,290 SULFATED llfl-METHYL ESTROGENS Ivar Laos, Skokie, and John S. Baran, Morton Grove, Ill., assignors to G. D. Searle & Co., Chicago, Ill. No Drawing. Filed Apr. 8, 1971, Ser. No. 132,557

Int. Cl. C07c 169/08 U.S. Cl. 260397.45 Claims ABSTRACT OF THE DISCLOSURE The above-captioned compounds are produced from 3- hydroxy 1lfl-methylestra-l,3,5(10)-trien-17-one by successive reactions with sulfamic acid in pyridine and an alkali metal hydroxide and are useful pharmacological agents, e.g. estrogens.

The present invention is concerned with sulfated 11,8- methyl estrogens. More specifically, it relates to alkali metal salts of 1lfi-methyl-17-oxoestra-1,3,5 (10)-trien-3-yl sulfate. These compounds are represented by the following structural formula wherein Z+ is an alkali metal ion or an ammonium ion and X is a carbonyl radical or a fl-hydroxymethylene radical. The alkali metals represented by the above formula are potassium, sodium, and lithium.

A most preferred starting material for the production of the instant compounds is 3-hydroxy-llfl-methylestra-LES, 5(10)-trien-l7-one. The preparation of this compound has been described previously in U.S. Pat. 3,346,602. When this compound is treated with sulfamic acid in pyridine, functioning as a catalyst and solvent, at a temperature of about 90 and then treated with the aqueous hydroxide of an alkali metal, the alkali metal salt of the 11/3- methyl-l7-oxoestra-1,3,5(10) -trien-3-yl sulfate is produced. The 17-hydroxy compound is produced forthwith by the reduction of the 17-ketone with a metallic hydride such as sodium borohydride.

The novel compounds of this invention display pharmacological, e. g. potent estrogenic, activity. The estrogenic utility of the instant compounds is evident from the results of a standardized test for their capacity to increase uterine weight in immature mice. The procedure is substantially the same as that described by Edgren, Proc. Soc. Exper. Biol. Med., 92, 569 (1956). White, female, 21-day old mice maintained on a synthetic, estrogen-free diet are used as test animals. To each of a group of 6-10 such animals, test compound, dissolved or suspended in corn oil, is administered subcutaneously or intragastrically on each of 3 successive days. Commonly, the initial total dose is 1 mg. of compound in 0.1 ml. of corn oil administered intragastrically in 3 equal portions. A second group of 6-10 animals likewise and concurrently administered corn oil alone serves as controls. The day after treatment is concluded, the animals are sacrificed; and the uteri are excised, dissected free of extraneous tissue, blotted to express contained fluid, and individually weighed. A compound is considered active if the mean uterine weight of the animals treated therewith significantly (P0.01) exceeds the mean uterine weight of the controls. Potency of an active compound, relative to estrone, is determined by repeating the test at progressively diminishing doses sufficient to fit a log dose response curve by the method of least squares to a corresponding curve for estrone developed 'by substituting 0.1 and 0.3 mcgm. of estrone, administered subcutaneously, for test compound in the foregoing procedure. From these curves, a dose of compound and a dose of estrone which produce an identical increase in mean uterine weight are selected, the second value is divided by the first, ,and the quotient is multiplied by 100 to give the percent potency.

The invention will appear more fully from the examples which follow. These examples are given by way of illustration only and are not to be construed as limiting the invention either in spirit or in scope as many modifications both in materials and methods will be apparent to those skilled in the art. In these examples temperatures are given in degrees centigrade C.) and quantities of materials in parts by weight unless otherwise noted.

EXAMPLE 1 To a suspension of 3.4 parts of pulverized sulfamic acid in 24.6 parts of dry pyridine, heated and stirred under a nitrogen atmosphere at about is added 2.84 parts of 3-hydroxy-1lp-methylestra-l,3,5(10)-trien 17 one in one portion. Heating and stirring of the reaction mixture at 90 is continued under a nitrogen atmosphere for 2 hours. After that time the reaction mixture is cooled to room temperature; 17.8 parts of anhydrous ether is added, and the precipitate is collected by filtration. After air drying, the precipitate is added to 25 parts by volume of a 12.5% aqueous potassium hydroxide solution and 12.3 parts of pyridine, and the mixture is shaken well. The aqueous layer is withdrawn and the organic layer is washed with ether. The resulting material which separates is then digested with a fresh portion of ether until the material turns crystalline. It is then recrystallized from methanol-ether solution to give the pure potassium salt, potassium llfl-methyl 17 oxoestra-1,3,5(10)-trien-3-yl sulfate. This compound is represented by the following structural formula.

EXAMPLE 2 By substituting an equivalent quantity of aqueous sodium hydroxide in the procedure of Example 1, there is obtained sodium 1lfi-methyl-17-oxoestra-1,3,5 10) -trien- 3-yl sulfate.

3 EXAMPLE 3 T o a solution of 1 part of sodium 1l;3-methyl-l7-oxo estra-1,3,5(lO)-trien-3-yl sulfate and 39.6 parts of methanol is added 0.5 part of sodium borohydride, and the reaction mixture is stirred at room temperature for about 1 hour. The solution is neutralized to pH 7 with dilute hydrochloric acid, and then made slightly alkaline to pH 8 with dilute sodium hydroxide solution. After evaporation to dryness under reduced pressure, a residual white solid is obtained. This material is dissolved in 60 parts of water, and the pH is readjusted to pH 8. The aqueous solution is then extracted with ether, and the pH of the solution is adjusted to 11. This mixture is extracted with n-butanol and the extract distilled to dryness. The pure material, sodium 17/3-hydroxy 115 methylestra-l,3,5(10)-trien-3-yl sulfate, is afforded upon recrystallization from aqueous acetone which contains a few parts of pyridine. This compound is represented by the following structural formula OH CH3 I l Na -i0 EXAMPLE 4 When an equivalent quantity of potassium llp-methyl- 17-oxoestra-l,3,5(10)-trien-3-yl sulfate is substituted in the procedure of Example 3, there is produced potassium 17fi-hydroxy-l 1fi-methylestra-1,3,5( -trien-3-yl sulfate.

4 What is claimed is: 1. A compound of the structural formula wherein Z is an alkali metal and X is a member of the group consisting of a carbonyl radical and ;3-hydr0xymethylene radical.

2. As in claim 1, the compound which is potassium 11,8- methyl-17-oxoestra-1,3,S 10) -trien-3-yl sulfate.

3. As in claim 1, the compound which is sodium methyl-17-oxoestra-1,3,S( l0)-trien-3-yl sulfate.

4. As in claim 1, the compound which is potassium 17B hydroxy 11 8 methylestra 1,3,5 (10)-trien-3-yl sulfate.

5. As in claim 1, the compound which is sodium hydroxy 11p methylestra 1,3,5(10) trien 3 yl sulfate.

References Cited UNITED STATES PATENTS 3,346,602 10/1967 Baran 260-397.45

OTHER REFERENCES Joseph et al.Steroids 7, pp. 577-87 (1966).

HENRY A. FRENCH, Primary Examiner US Cl. X.R. 

